REVIEW ARTICLEpublished: 05 April 2013

doi: 10.3389/fphys.2013.00063

Caught in the thickness of brain fog: exploring thecognitive symptoms of Chronic Fatigue SyndromeAnthony J. Ocon*

Departments of Physiology/Medicine, Center for Hypotension, New York Medical College, Valhalla, NY, USA

Edited by:

Julian Mark Stewart, New YorkMedical College, USA

Reviewed by:

Kathleen S. Curtis, Oklahoma StateUniversity - Center for HealthSciences, USARyo Kitada, National Institute forPhysiological Sciences, Japan

*Correspondence:

Anthony J. Ocon, Departments ofPhysiology/Medicine, Center forHypotension, New York MedicalCollege, 19 Bradhurst Ave., Suite1600S, Hawthorne, NY 10532, USA.e-mail: anthony_ocon@nymc.edu

Chronic Fatigue Syndrome (CFS) is defined as greater than 6 months of persistent fatiguethat is experienced physically and cognitively. The cognitive symptoms are generallythought to be a mild cognitive impairment, but individuals with CFS subjectively describethem as “brain fog.” The impairment is not fully understood and often is described asslow thinking, difficulty focusing, confusion, lack of concentration, forgetfulness, or ahaziness in thought processes. Causes of “brain fog” and mild cognitive impairment havebeen investigated. Possible physiological correlates may be due to the effects of chronicorthostatic intolerance (OI) in the form of the Postural Tachycardia Syndrome (POTS) anddecreases in cerebral blood flow (CBF). In addition, fMRI studies suggest that individualswith CFS may require increased cortical and subcortical brain activation to completedifficult mental tasks. Furthermore, neurocognitive testing in CFS has demonstrateddeficits in speed and efficiency of information processing, attention, concentration, andworking memory. The cognitive impairments are then perceived as an exaggerated mentalfatigue. As a whole, this is experienced by those with CFS as “brain fog” and may beviewed as the interaction of physiological, cognitive, and perceptual factors. Thus, thecognitive symptoms of CFS may be due to altered CBF activation and regulation that areexacerbated by a stressor, such as orthostasis or a difficult mental task, resulting in thedecreased ability to readily process information, which is then perceived as fatiguing andexperienced as “brain fog.” Future research looks to further explore these interactions,how they produce cognitive impairments, and explain the perception of “brain fog” froma mechanistic standpoint.

Keywords: Chronic Fatigue Syndrome, postural orthostatic tachycardia syndrome, neurocognition, cerebral blood

flow (CBF), functional magnetic resonance imaging (fMRI), brain fog, orthostatic intolerance

INTRODUCTIONChronic Fatigue Syndrome (CFS) is a clinically defined set ofsymptoms of unknown etiology most notable for persistentfatigue lasting greater than 6 months. In 1994, the Center forDisease Control and Prevention (CDC) uniformly defined CFS.The CDC requiring the fatigue to be of new onset, non-exertional,not improved with rest, and debilitating to a person’s lifestyle(Fukuda et al., 1994). Additionally, at least four of the follow-ing symptoms must be concurrently present: pharyngeal pain,cervical or axillary lymphadenopathy, myalgia, polyarthritis with-out erythema or edema, headache, non-restful sleep, prolongedpost-exercise fatigue, and/or debilitating cognitive impairmentsin short-term memory and concentration (Fukuda et al., 1994).While the exact symptoms of each case of CFS are heteroge-neous, up to 85% of individuals describe experiencing cogni-tive impairments (Komaroff, 1993). These cognitive impairmentshave subjectively been described by patients with CFS as “brainfog.” Descriptions of “brain fog” include slow thinking, diffi-culty focusing, confusion, lack of concentration, forgetfulness, ora haziness in thought processes. In fact, “brain fog” may be oneof the most debilitating aspects of CFS (Jain and DeLisa, 1998;Natelson and Lange, 2002; Afari and Buchwald, 2003; Jorgensen,

2008). However, a precise definition of CFS “brain fog” hasyet to be formulated. Thus, “brain fog” may be conceptionallydefined as the perception and experience of mental fatigue thatis associated with and related to mild cognitive impairments inCFS. Research has focused on describing “brain fog” and mildcognitive impairment in regards to CFS using objective measure-ments. Physiologically, areas of study have investigated mentalfatigue and impairment as the effects of orthostatic stress, inrelationship to changes in cerebral blood flow (CBF), and asa perception. In addition, neurocognitive testing has localizedthe cognitive impairments in CFS to the domains of attention,information processing, memory, and reaction time (Cockshelland Mathias, 2010). Furthermore, functional magnetic resonanceimaging (fMRI) of the brain has associated changes in anatomicalstructures to the cognitive fatigue experienced in CFS. However,while much research has been done to analyze the individualcomponents of the cognitive symptoms in CFS, no single sourcehas compiled a comprehensive description of the multiple factorsand their interactions that may play a role in the CFS patient’sexperience of “brain fog” (see Figure 1). Thus, to better under-stand cognitive impairment and “brain fog” in CFS, as well asto guide future research, the goal of this review is to summarize,

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Ocon Brain fog in CFS

FIGURE 1 | Interactions between multiple factors may contribute to

the cognitive symptoms subjectively described as “brain fog” in

Chronic Fatigue Syndrome (CFS). POTS, Postural Tachycardia Syndrome.

standardize, and analyze the cognitive symptoms which lead toimpairment.

NEUROCOGNITIVE TESTING DEMONSTRATES SPECIFICCOGNITIVE DEFICITS IN CFSIf “brain fog” truly is the subjective experience of cognitiveimpairment in CFS, the impairment should be measurable. Earlywork using sensory and cognitive event-related potentials broadlydemonstrated deficits in CFS subjects compared to control sub-jects in areas of memory, concentration, attention, informationprocessing, and reaction time (Prasher et al., 1990). Research hasattempted to use more focused tests to narrow in on what exactlythese deficits are. A table of cognitive tests that have been used tostudy impairments in CFS is listed (see Table 1).

Using the Paced Auditory Serial Addition Test (PASAT) andthe Digit Span Test, tests of memory, attention, and data pro-cessing, DeLuca et al. (1993) found that CFS subjects scoredlower than control subjects, suggesting deficits in informa-tion processing of complex material. Further work by DeLucaet al. (1995) showed that CFS subjects have intact memorystorage, consolidation, and retrieval and “higher order” cog-nitive function; however, they exhibit decreased speed andefficiency in information processing, especially with auditorymaterial, and subjectively perceive a more generalized cogni-tive impairment (DeLuca et al., 1995). Interestingly, this per-ception of generalized cognitive impairment fits the concept of“brain fog.”

Table 1 | List of cognitive tests used to study Chronic Fatigue

Syndrome cognitive impairments.

Name of test used References

Paced auditory serial addition test DeLuca et al., 1993, 1995

Digit span test DeLuca et al., 1993, 1995

Trail making test DeLuca et al., 1995

Booklet category test DeLuca et al., 1995

Rey complex figure test DeLuca et al., 1995

California verbal test DeLuca et al., 1995

Wechsler adult intelligence scale revised DeLuca et al., 1995

Logical memory subtest of the Wechslermemory scale revised

DeLuca et al., 1995

Beck depression inventory Grafman et al., 1993;DeLuca et al., 1995

Wechsler adult intelligence scale revised Grafman et al., 1993

Simple reaction time test Grafman et al., 1993

Serial reaction time test Grafman et al., 1993

Time wall test Grafman et al., 1993

Time clock test Grafman et al., 1993

Tower of London Grafman et al., 1993

Tower of Hanoi Grafman et al., 1993

Twenty questions test Grafman et al., 1993

Wechsler memory scale revised Grafman et al., 1993

Experimental paired associate test Grafman et al., 1993

Hasher frequency monitoring task Grafman et al., 1993

Story memory test Grafman et al., 1993

Word fluency test Grafman et al., 1993

Somatization scale Grafman et al., 1993

Neurobehavioral rating scale Grafman et al., 1993

Fatigue scale Grafman et al., 1993

Cambridge neuropsychological testautomated battery

Joyce et al., 1996;Capuron et al., 2006

Digit span forward test Dobbs et al., 2001

Digit span backward test Dobbs et al., 2001

Trails A test Dobbs et al., 2001

Trails B test Dobbs et al., 2001

n-back test Caseras et al., 2006;Ocon et al., 2012;Stewart et al., 2012

Finger tapping task Cook et al., 2007

Auditory monitoring task Cook et al., 2007

Motor imagery task de Lange et al., 2004

Control visual imagery task de Lange et al., 2004

In addition to information processing, deficits in memoryhave been studied in CFS. Work by Grafman et al. (1993) com-pared responses to a battery of memory and neuropsychologicaltests (see Table 1) between CFS and control subjects. While over-all memory consolidation and storage were intact, CFS subjectsdemonstrated selective deficits in memory processing (Grafmanet al., 1993). Joyce et al. (1996) used the Cambridge neuropsy-chological test automated battery (CANTAB), which is a set oftests that measure various aspects of memory, attention, reactiontime, executive functioning, and decision making, and found that

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CFS subjects exhibited deficits in working memory and impairedattention. Working memory may be defined as a transient cogni-tive storage system that is able to process information and use itto complete a task (Baddeley, 1986). Similarly, Dobbs et al. (2001)reported that CFS subjects had working memory deficits basedon results from the Digit Span Forward test, Digit Span Backwardtest, Trails A test, and Trails B test, which are a set of memory andattention tests. These deficits were mainly apparent during chal-lenging tasks that needed sustained attention and efficient mentalprocessing (Dobbs et al., 2001). Work by Capuron et al. (2006),using the CANTAB, further distinguished that working memoryand impaired attention were only impaired compared to controlsubjects in a subgroup of CFS patients who subjectively statedexperiencing increased mental fatigue. When they compared CFSwho did not report mental fatigue, they did not find a difference(Capuron et al., 2006).

Of note, children with CFS have also been studied and havebeen shown to exhibit cognitive impairment in the areas of focus-ing, splitting, switching attention, working memory, and auditorylearning (Haig-Ferguson et al., 2009). Interestingly, a recent studyin children with CFS found that treatment with both cognitivebehavioral therapy and pharmacotherapy lead to improvementsin attention (Kawatani et al., 2011).

In summary, research has demonstrated cognitive impairmentin CFS, particularly in working memory, information process-ing, attention, and reaction time. Deficiencies in these cognitiveareas may be perceived on a day-to-day basis as “brain fog.”Mental fatigue is necessary and must be experienced in orderfor CFS subjects to have cognitive symptoms. Comprehensively,the cognitive impairments associated with CFS impair the abil-ity to maintain attention for an extended period of time, dis-rupt efficient and speedy information processing, and resultsin an inability to plan or order responses from memory (Joyceet al., 1996). Functionally, this is translated into increased reac-tion time while completing tasks. The deficits in informationprocessing and working memory are similar and most likelyrelated. Task difficulty plays a role in the perception of mentalfatigue, with CFS subjects feeling most fatigued following themore difficult tasks. Additionally, the greatest degree of impair-ment and disability has been noted in CFS subjects who per-form the worst on neurocognitive tests (Christodoulou et al.,1998).

PSYCHIATRIC COMORBIDITIES ARE NOT ASSOCIATED WITHCOGNITIVE IMPAIRMENT IN CFSDepression and anxiety often co-exist in subjects with CFSand may in themselves be associated with cognitive impairment(Afari and Buchwald, 2003). Studies have focused on determin-ing whether comorbid psychiatric illness is the cause of cognitiveimpairment in CFS.

An early study prior to the 1994 CDC definition suggested thatsubjective cognitive impairment in individuals with CFS may beassociated with depression (McDonald et al., 1993). However, astudy by DeLuca et al. (1997) suggested otherwise. This groupseparated CFS subjects into a cohort with psychiatric comorbidityand a cohort without. When compared to healthy control sub-jects’ performance on neurocognitive tests, CFS subjects without

psychiatric comorbidities exhibit neurocognitive impairment,whereas those with comorbidities did not (DeLuca et al., 1997).More recent work by the same group similarly concluded thatCFS subjects without psychiatric comorbidities exhibit deficitsin working memory and information processing, while thosewith psychiatric comorbidities were not different from controls(DeLuca et al., 2004). Further work by other groups similarly hasconcluded that the cognitive impairment in CFS is not due todepression (Constant et al., 2011; Santamarina-Perez et al., 2011).

From these studies, two distinct groups of CFS subjectshave been identified. It appears that cognitive symptoms occuronly in CFS subjects without psychiatric comorbidities. Morestudies are needed to elucidate the factors which may explainthis. There is a clear need in future studies to appropriatelystratify CFS subjects into those with and without psychiatriccomorbidities.

ORTHOSTATIC STRESS IMPAIRS COGNITIVE PERFORMANCEIN CFSCognitive impairment has been associated with the physiologicalonset of orthostatic intolerance (OI). OI is defined by the onset ofsigns and symptoms that occur when an individual assumes theupright posture, with the signs and symptoms being alleviated byresuming the supine position. Rowe et al. (1995) first describedOI in CFS in 1995. Both adults and adolescents with CFS oftenexperience OI in the form of the Postural Tachycardia Syndrome(POTS), with syncope being less common (De et al., 1996; Roweand Calkins, 1998; Stewart et al., 1999; Karas et al., 2000; Hoadet al., 2008). POTS is defined in adults as symptomatic OIwith an increase in HR of at least 30 beats per minute (bpm)or a maximum HR of 120 bpm (Schondorf and Low, 1993).Typical symptoms of OI that occur include dizziness, neurocog-nitive impairment, tremulousness, nausea, and long-term fatigue(Schondorf and Freeman, 1999; Medow and Stewart, 2007). Someindividuals with POTS experience migraine headaches (Piovesanet al., 2008). While standing upright, physiologic changes notedin POTS include increased diastolic BP and total peripheral resis-tance, decreased stroke volume, and impaired venoconstriction(Low et al., 1994). Regional venous blood pooling may occurwhile upright, particularly in the splanchnic region and in thelegs (Stewart and Montgomery, 2004). POTS subjects tend tohave decreased total blood volumes, red cell volume, and plasmaaldosterone (Raj et al., 2005). About half of the individuals withPOTS exhibit orthostatic hyperventilation and hypocapnia, whilethe other half breathe normally and are eucapnic (Stewart et al.,2006). A similar respiratory pattern of orthostatic hypocapnia hasbeen noted in about a third of CFS subjects (Naschitz et al., 2000,2006; Natelson et al., 2007).

Limited psychological testing has occurred in POTS subjects.Work by Raj et al. (2009) found mild depression and moderateanxiety to be prevalent in POTS subjects, but lifetime preva-lence of psychiatric diseases overall was not different than thatof control subjects. They determined that the anxiety experiencedin POTS was more related to the symptoms of the disease andhow those symptoms may affect the individual (Raj et al., 2009).Similar to CFS, POTS subjects may also experience attentiondeficits (Raj et al., 2009).

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Moreover, some of the symptoms of CFS and POTS overlapin their clinical descriptions as well as in their associations withcognitive impairment, and individuals commonly present withsymptoms of both syndromes (De et al., 1996; Hoad et al., 2008).Of note, some individuals with CFS and/or POTS also suffer fromEhlers–Danlos Syndrome, a genetic disorder that causes a defectin the synthesis of collagen which affects connective tissue (Roweet al., 1999; Mathias et al., 2012). This syndrome may predisposeto OI due to the occurrence of excessive venous pooling becauseof exaggerated venous wall distention and dysfunctional venousvalves (Rowe et al., 1999).

Neurocognitive impairment is often described as a symptomof OI. The subjective descriptions of the cognitive impairmentsin POTS are similar to those in CFS. Therefore, OI, in partic-ular POTS, may be connected to the “brain fog” experiencedin CFS. Limited work has looked at neurocognitive testing dur-ing orthostatic stress. One study by Karas et al. (2000) foundthat adolescents with POTS experience cognitive impairment,although no formal neurocognitive testing was used to deter-mine the exact areas that were affected. Using more objectivemeasures, work by Ocon et al. (2012) studied subjects with bothCFS and POTS (CFS/POTS) during graded orthostatic stress,using a n-back task as a cognitive stressor. The n-back task is acognitive test of progressively increasing difficulty that stressesdomains of working memory and information processing whilemeasuring reaction time (Braver et al., 1997). Results showedthat subject with CFS/POTS exhibited no differences in accu-racy or reaction time compared to control subjects while supine(Ocon et al., 2012). However, during moderate to severe lev-els of orthostatic stress, CFS/POTS subjects were less accurateand had a longer reaction time compared to control subjects,particularly during the difficult stages of the n-back task (Oconet al., 2012). This study demonstrated that orthostatic stressmay impair the cognitive abilities of those with CFS/POTS,especially during difficult tasks. Thus, working memory, infor-mation processing, and reaction time may be impaired withprolonged orthostatic stress. These cognitive deficiencies may beperceived as “brain fog.” Speculatively, one may consider phys-iological changes during orthostasis to potentially be a cause ofthe cognitive impairment. In particular, alterations in CBF reg-ulation may be related to the cognitive symptoms as describedbelow.

CEREBRAL BLOOD FLOW IS DECREASED IN CFSMuch research has studied CBF alterations in CFS. Early workmeasured regional CBF using single photon emission computedtomography (SPECT) in those with CFS. Ichise et al. (1992)found that 80% of CFS subjects exhibited decreased regionalCBF particularly in the frontal, temporal, parietal, occipital, andbasal ganglia regions compared to control subjects without CFSor other neurological/neuropsychiatric disorders. Similarly usingSPECT, Schwartz et al. (1994) found decreased regional CBF inCFS subjects in the frontal and temporal lobes. Costa et al. (1995)studied brainstem perfusion in CFS subjects and found hypoper-fusion compared to both control subjects and subjects with majordepression. However, work by Fischler et al. (1996) did not findsignificant differences in regional CBF between CFS and control

subjects, and MacHale et al. (2000) actually found increased CBFin CFS subjects in the thalamus, pallidum, and putamen regions.Technical differences with SPECT and methodological incon-sistencies between studies may account for the contradictoryresults.

Other techniques of measuring CBF have been applied todetermine whether decreased CBF does occur in CFS. Positronemission tomography was used by Tirelli et al. (1998) to look atcerebral metabolism in CFS subjects. They found that CFS sub-jects exhibited hypometabolism in the right mediofrontal cortexand brainstem compared to control subjects (Tirelli et al., 1998).Near-infrared spectroscopy (NIRS) is another method whichlooks at changes in brain oxygenation of hemoglobin. NIRS mea-surements by Tanaka et al. (2002) found that CFS subjects hadlower brain oxy-hemoglobin while standing upright compared tocontrol subjects. This suggests that orthostatic stress may neg-atively influence cerebral oxygenation in CFS. Similarly, Patricket al. (2008) used NIRS during maximal incremental cycle exercisein female CFS subjects. They found that the CFS subjects exhib-ited exercise intolerance that was associated with decreased pre-frontal oxygenation (Patrick et al., 2008). Additionally, Natelsonet al. used more advanced imaging techniques of Xenon gasdiffusion computerized tomography (Yoshiuchi et al., 2006)and magnetic resonance arterial spin labeling (Biswal et al.,2011) to demonstrate reduced total CBF in CFS subjects com-pared to controls, especially in CFS subjects without psychiatriccomorbidities.

In order to study whether altered CBF affected cognitive per-formance, Schmaling et al. (2003) used SPECT measurementsof CBF during the PASAT test to see whether impaired CBF inCFS could be associated with decreased cognitive impairment.Prior to testing, CFS subjects had decreased perfusion in theanterior cingulate region of the brain compared to control sub-jects (Schmaling et al., 2003). During testing, there was a greaterincrease in blood flow to the left anterior cingulate region inCFS subjects (Schmaling et al., 2003). Furthermore, CFS sub-jects exhibited a wide-spread, diffuse pattern of CBF in the frontallobe, temporal lobe, and thalamus compared to a small, focal pat-tern in the right frontal lobe and right temporal lobe in controlsubjects (Schmaling et al., 2003). No differences in test per-formance occurred between groups, but CFS subjects reportedgreater mental fatigue following testing. This suggested that anincreased change in cerebral perfusion with greater activation ofmore brain regions was necessary for CFS subjects to perform atthe same level as that of control subjects (Schmaling et al., 2003).This may be due to the need to overcome the decreased baselineCBF. These subjects also subjectively experienced “brain fog” asmental fatigue, suggesting that the increased change in cerebralperfusion and activation during cognitive tasks was perceived asstressful and exaggerated exhaustion. Speculatively, this may berelated to altered cerebral metabolism, with increased productionof metabolites affecting neuronal biochemical pathways. Furtherresearch measuring cerebral metabolism during neurocognitivetesting is needed to detail the processes of mental fatigue andimpairment in CFS.

As mentioned above, orthostatic stress is related to neurocog-nitive impairments in CFS and POTS and may induce changes

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in CBF. Since some POTS symptoms overlap with CFS, it isimportant to look at how CBF is affected in this syndrome.In most studies, CBF was estimated by measurements of CBFvelocity (CBFv) using transcranial Doppler sonography. Work byNovak et al. (1998) found that during orthostatic stress, POTSsubjects have decreased CBFv. This may be related to hyper-ventilation and hypocapnia-induced increased cerebrovascularresistance (Novak et al., 1998). Similarly, Low et al. (1999) sug-gested that the altered CBFv in POTS was explained solely byrespiratory changes and their concomitant affect on cerebrova-somotor tone. Other research suggested that ineffective cerebralautoregulation also played a role in the decreased CBFv seen inPOTS (Jacob et al., 1999; Hermosillo et al., 2002). Ocon et al.(2009) found a relationship between decreased CBFv and alteredcerebral autoregulation in a cohort of POTS subjects who wereeucapnic during orthostatic stress. However, Schondorf et al.(2005) reported normal cerebral autoregulation in POTS sub-jects, though the group did not measure changes in CO2. Thus,CBF appears to be decreased in POTS subjects similarly to howit is decreased in CFS subjects, but the mechanisms involved arecontroversial and probably multifactorial. The decreased CBF inPOTS and CFS during orthostatic stress may play a role in theirperceived cognitive impairment.

To study this, work by Stewart et al. (2012) looked at howCBFv changed during increasing mental and orthostatic stress ina group of subjects with both CFS and POTS. Mental stress wasinduced by the n-back task, while orthostatic stress was inducedwith graded tilt-table testing. In control subjects, CBFv increasedas the level of n-back difficulty increased, independent of ortho-static stress (Stewart et al., 2012). In contrast, CFS/POTS subjectsdid not exhibit an increase in CBFv with increasing n-back dif-ficulty. Additionally, decreasing CBFv in CFS/POTS subjects wasdependent on the level of orthostatic stress (Stewart et al., 2012).This study concluded that control subjects demonstrated appro-priate neurovascular coupling to mental stress, whereas CBFv isnot activated by mental stress in CFS/POTS subjects (Stewartet al., 2012). This may be due to an uncoupling of cognitive–vasomotor interactions (Stewart et al., 2012). Additionally, super-imposed orthostatic stress appears to further negatively impactthe cerebral vasomotor responses to mental stress in CFS/POTSsubjects (Stewart et al., 2012).

Therefore, cognitive impairments in CFS/POTS may be relatedto impaired activation and regulation of CBF, especially duringchallenging mental tasks and orthostatic stress. Adequate cerebralperfusion is necessary for the brain to function. In those with CFSand/or POTS, a gradual and chronic hypoperfusion of the brainmay occur, especially during orthostatic stress (Ocon et al., 2009).Animal studies suggest that chronic cerebral hypoperfusion maycause cognitive impairment (Ni et al., 1994; Liu et al., 2012). Thus,if CBF is decreased chronically in CFS, mild cognitive impairmentmay be the result.

FUNCTIONAL MRI FINDS ALTERED REGIONAL CEREBRALACTIVATION IN CFSCerebral imaging techniques have tried to associate cognitiveimpairments with specific cerebral regions. An early MRI study byLange et al. (1999) found increased hyperintensities in the frontal

lobe subcortical white matter of CFS subjects without psychiatriccomorbidities compared to those with comorbidities and controlsubjects, suggesting nonspecific cerebral lesions as the basis forcognitive impairment. Using fMRI to measure cerebral changesduring cognitive tasks (see Table 1), de Lange et al. (2004) foundthat CFS subjects exhibited decreased caudate nucleus activity,increased recruitment of cerebral regions, and an inactive ventralanterior cingulated cortex during errors compared to control sub-jects. They suggested that these changes may be associated withfatigue, the need for additional neural activation to complete atask, and reduced motivation (de Lange et al., 2004). Additionalwork using fMRI found that demanding working memory taskselicited activation in more regions of the brain in CFS subjectsthan in control subjects (Lange et al., 2005). It is tempting to spec-ulate that CFS subjects may require more brain activation duringworking memory tasks. Consistent with this speculation, Caseraset al. (2006) used the n-back task to monitor how CFS subjects’brains respond to different levels of mental stress compared tocontrol subjects. They found that during lower difficulty n-backtesting, CFS patients exhibited increased activation of workingmemory centers (Caseras et al., 2006). However, during higherdifficulty testing, they had decreased activation compared to con-trol subjects (Caseras et al., 2006). Similarly, Cook et al. (2007)showed that CFS subjects, when compared to control subjects,have increased cortical and subcortical cerebral activation dur-ing fatiguing, stressful mental tasks (see Table 1). They suggestedthat increased brain activation may be related to the perception ofmental fatigue (Cook et al., 2007).

PHYSICAL AND COGNITIVE SYMPTOMS OF CFS MAY BE AMENTAL PERCEPTION OF STIMULIPrior to the 1994 CDC definition of CFS, Kent-Braun et al.(1993) theorized that the physical symptoms of fatigue in CFSwere in part related to a central nervous system perception ofthe body’s response to a stressor. They hypothesized that CFSdid not induce true muscle fatigue, but rather the experience offatigue was a mental discernment of peripheral sensations andstimuli. To test this hypothesis, the group studied muscle fatiguein the tibialis anterior muscle following exercise. They foundthat CFS subjects failed to voluntarily activate the muscle afterprolonged stress, despite no detectable metabolic or functionalchanges having occurred (Kent-Braun et al., 1993). This sug-gested that in CFS bodily fatigue during and following exercisewas perceived mentally rather than there being true peripheralmuscle exhaustion. Another study further examined fatigue as aperception. While studying post-exertion fatigue in females withCFS, Sisto et al. (1998) found that the experience of fatigue fol-lowing exercise was exaggerated compared to control subjects,and it may experienced in a prolonged manner for 12–14 days.Together, these studies suggest that the perception of fatigue inCFS is a mental experience of physical fatigue following exercise,or potentially any a stressful stimulus, even if no such physi-cal exhaustion occurs. In addition to the cognitive component,this mental experience is part of the subjective “brain fog” thatpatients with CFS describe. This perception may be exaggerated,continual, and prolonged, despite true muscle exhaustion notoccurring.

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In an attempt to detail a mechanism describing the percep-tion of fatigue in CFS, recent work has looked at neuroactiveamino acids and metabolite concentrations following exercise. Astudy found increased tryptophan, decreased branch chain aminoacids, and decreased tyrosine following exercise in the plasmaof CFS subjects compared to controls (Georgiades et al., 2003).The exact meaning of these changes is difficult to discern, butspeculatively this may suggest that metabolic alterations in pre-curors involved in the serotonergic and dopaminergic pathwaysmay be involved in the central perception of fatigue. Moreover,another study showed that CFS subjects exhibit electroencephalo-gram changes during fatiguing exercise. Again, how this relatesto the perception of fatigue is speculative, but it may suggestthat altered cerebral signaling, particularly that involved withmotor activity, may be experienced as mental fatigue (Siemionowet al., 2004). Further work is needed to determine how mentalfatigue, cognitive impairment, and the subjective experience of“brain fog” relate biochemically, physiologically, and mechanisti-cally to the changes that occur in CFS following exercise or anystressor.

THE EXPERIENCE OF “BRAIN FOG” IN CFS AS A COLLECTIONOF PHYSIOLOGICAL, COGNITIVE, AND PERCEPTUALFACTORSOver the past 20 years, research has answered many questionsregarding cognitive symptoms in CFS. The experience of “brainfog” in those with CFS appears to be the conscious perception ofcognitive impairment and is related to mental fatigue. Individualswith CFS do not exhibit complete cognitive disability or demen-tia. However, they may experience deficits in working memory,information processing, and attention, which then may translateinto a longer reaction time during tasks. It is logical that the per-ception of such deficits would be described as mental cloudinessand difficulty thinking.

Drawing from an overview of the above studies, cognitiveimpairment in CFS is exacerbated by stressful stimuli suchas a difficult mental task, exercise, and/or orthostatic stress.Physiologically, the cognitive impairments may be associatedwith impaired cardiovascular hemodynamics as seen in POTS,

decreased total CBF, and altered activation of CBF during mentaltasks. Psychiatric diseases do not seem to be related to cogni-tive impairment. Importantly, the perception of the symptomsof CFS is often exaggerated and excessive compared to what ismeasured. Aside from the cognitive impairments noted above,this perception may be disabling. Thus, “brain fog” is caused bymeasurable cognitive impairments but also the more subjectiveperception of mental fatigue and its impact on the individualwith CFS. As shown in Figure 1, interactions of multiple factorsclearly play a role. Based on the above research, one specula-tive view of the mechanisms behind the cognitive symptoms ofCFS is that altered CBF activation and regulation are exacerbatedby a stressor, such as orthostasis or a difficult mental task, thatresults in the decreased ability to readily process information,which is then perceived as fatiguing and experienced as “brainfog.” Thus, future research will study if interventions that mod-ify CBF affect the cognitive symptoms of CFS. Additionally, morework will look at how orthostatic stress impacts neurocogni-tion. Finally, since the impaired cognitive domains in CFS havebeen determined, interventions to improve these domains will betested.

To date, treatment of CFS has been focused on improvingthe physical fatigued state rather than the cognitive impairment.Meta-analyses demonstrate that cognitive behavioral therapy andgraded exercise therapy effectively treat CFS in many individuals(Edmonds et al., 2004; Price et al., 2008). It would not be sur-prising if mental fatigue also is improved with such therapies, butfuture studies are necessary to formally determine this.

ACKNOWLEDGMENTSMuch gratitude is given toward the members of the ResearchDivision of Pediatric Cardiology at New York Medical College,especially Dr. Julian Stewart, Dr. Marvin Medow, and the mem-bers of their laboratory. Additional thanks goes to Department ofPhysiology at New York Medical College.

GRANTSThis work was supported by the National Heart, Lung, and BloodInstitute Grants 1-F30-HL-097380.

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Conflict of Interest Statement: Theauthor declares that the researchwas conducted in the absence of anycommercial or financial relationshipsthat could be construed as a potentialconflict of interest.

Received: 26 December 2012; accepted:15 March 2013; published online: 05April 2013.Citation: Ocon AJ (2013) Caught inthe thickness of brain fog: exploring thecognitive symptoms of Chronic FatigueSyndrome. Front. Physiol. 4:63. doi:10.3389/fphys.2013.00063This article was submitted to Frontiersin Integrative Physiology, a specialty ofFrontiers in Physiology.Copyright © 2013 Ocon. This is anopen-access article distributed underthe terms of the Creative CommonsAttribution License, which permits use,distribution and reproduction in otherforums, provided the original authorsand source are credited and subject to anycopyright notices concerning any third-party graphics etc.

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